What is the recommended approach to evaluate and treat a patient with chronic interstitial lung disease, including history, imaging, pulmonary function testing, and pharmacologic management?

Evaluation and Treatment of Chronic Interstitial Lung Disease

For chronic interstitial lung disease, obtain high-resolution CT chest as the diagnostic gold standard, perform comprehensive pulmonary function testing including spirometry with FVC, TLC, and DLCO, and initiate antifibrotic therapy with nintedanib or pirfenidone for idiopathic pulmonary fibrosis or mycophenolate mofetil for connective tissue disease-associated ILD, with all cases requiring multidisciplinary discussion integrating clinical, radiological, and pathological findings.

Initial Clinical Assessment

History Taking - Critical Elements

Environmental and occupational exposure history is the single most important factor for achieving optimal outcomes and must be comprehensively documented 1, 2:

• Document specific mold exposures, air pollution, and occupational vapors, gases, dusts, and fumes - these interact with genetic susceptibility as causative drivers 3, 4
• Obtain detailed medication history - drug-induced ILD accounts for a significant proportion of cases 2
• Assess for recreational/avocational exposures including hobbies and home environment 2
• Evaluate for connective tissue disease symptoms - CTD accounts for 25% of all ILD cases 5, 4
• Document family history of pulmonary fibrosis - 15-30% of first-degree relatives of patients with familial pulmonary fibrosis have interstitial lung abnormalities 3, 4
• Record smoking history - approximately 8% of smokers undergoing lung cancer screening have ILD 4, 6

Physical Examination - Specific Findings

• Auscultate for fine, dry, "Velcro-type" end-inspiratory crackles - present in >80% of IPF patients, initially at lung bases 4
• Examine for digital clubbing - present in 25-50% of IPF patients 4
• Assess for cyanosis indicating severe gas exchange impairment in late-stage disease 4
• Palpate for right ventricular heave suggesting cor pulmonale in advanced disease 4
• Check for peripheral edema indicating right heart failure 4

Critical pitfall: Do not attribute cough and dyspnea solely to ILD without excluding cardiac disease, asthma, and postnasal drainage 4.

Diagnostic Imaging

High-Resolution CT Chest

HRCT is the gold standard for ILD diagnosis with 95.7% sensitivity for detecting ILD with ≥20% lung involvement and must be performed in all suspected cases 4, 5:

• Obtain inspiratory prone images and supine end-expiratory imaging 4
• HRCT has 91% sensitivity and 71% specificity for diagnosing ILD subtypes 5
• Usual interstitial pneumonia pattern shows patchy subpleural ground-glass opacity, irregular lines, and honeycombing 7
• Nonspecific interstitial pneumonia shows patchy or diffuse ground-glass opacity with consolidation and irregular lines 7

Chest radiography alone is insufficient - up to 10% of ILD patients have normal chest X-rays 4.

Pulmonary Function Testing

Baseline PFTs are mandatory to establish a baseline for future comparison and identify early ILD 4, 8:

• Spirometry to identify restrictive pattern with decreased FVC 4
• Total lung capacity (TLC) to confirm restriction 4
• Diffusion capacity (DLCO) to assess gas exchange impairment 4
• 6-minute walk test to evaluate exercise capacity and oxygen desaturation 4

Baseline FVC <80% has only 47.5% sensitivity for detecting ILD, emphasizing the need for imaging 4.

A 5% decline in FVC over 12 months is associated with approximately 2-fold increase in mortality 5.

Laboratory Evaluation

Obtain the following blood tests 4:

• Complete blood count with differential, C-reactive protein, serum creatinine, transaminases, gamma-glutamyltransferase, and alkaline phosphatases 4
• Autoimmune serologies including anti-nuclear antibodies, anti-citrullinated cyclic peptide antibodies, and rheumatoid factor 4

Echocardiography

Echocardiography is strongly recommended as part of initial evaluation to rule out structural cardiovascular disease and pulmonary hypertension 3:

• Cardiac and vascular anomalies are detected in up to 9% of children suspected of having ILD 3
• Up to 85% of individuals with end-stage fibrotic ILD develop pulmonary hypertension 5
• Pulmonary hypertension is associated with worse prognosis 3

Bronchoalveolar Lavage

When HRCT and clinical findings are insufficient for definitive diagnosis, BAL cellular analysis provides diagnostic clues 3, 4:

• Lymphocyte differential count >25% suggests granulomatous disease (sarcoidosis, hypersensitivity pneumonitis, chronic beryllium disease), cellular NSIP, drug reaction, or cryptogenic organizing pneumonia 3
• Lymphocyte count >50% suggests hypersensitivity pneumonitis or cellular NSIP 3
• Eosinophil count >25% is virtually diagnostic of acute or chronic eosinophilic pneumonia 3
• CD4/CD8 ratio >4 is highly specific for sarcoidosis in the absence of increased proportion of other inflammatory cell types 3

Tissue Diagnosis

When HRCT and clinical findings are insufficient for definitive diagnosis, transbronchial lung cryobiopsy (TBLC) is suggested as first-line biopsy method 4:

• TBLC provides larger samples without crush artifacts compared to traditional transbronchial lung biopsy 4
• TBLC has lower complication rates than surgical lung biopsy 4
• Surgical lung biopsy may be necessary in rapidly progressive cases or when TBLC is non-diagnostic 3

Multidisciplinary Discussion

Multidisciplinary discussion involving pulmonologists, radiologists, and pathologists is mandatory for optimal diagnostic yield 4, 2:

• MDD must integrate clinical, radiological, and pathological findings to establish final diagnosis 4
• In 77 patients where MDD consensus diagnosis differed from referring diagnosis, assessment of environmental exposures and medical history was retrospectively the most impactful factor 2
• HRCT and histopathology patterns (UIP, NSIP, organizing pneumonia) are often nonspecific and associated with multiple clinical diagnoses 2

Pharmacologic Management

Idiopathic Pulmonary Fibrosis

For IPF, initiate antifibrotic therapy with nintedanib or pirfenidone - these agents slow annual FVC decline by 44-57% 8, 9, 5:

• Pirfenidone 2,403 mg/day administered three times daily with food demonstrated statistically significant reduction in FVC decline at 52 weeks 9
• Do not use immunosuppressive therapy for IPF - it is not effective and may be harmful 8

Connective Tissue Disease-Associated ILD

For most CTD-ILD patients (except SSc-ILD), initiate mycophenolate mofetil, azathioprine, rituximab, or cyclophosphamide as first-line treatment 4, 8, 5:

• Mycophenolate mofetil is the preferred first-line immunosuppressive therapy for CTD-ILD 8
• Avoid glucocorticoids as first-line treatment in SSc-ILD (strong recommendation against) 4
• Tocilizumab is conditionally recommended as first-line option for SSc-ILD and mixed connective tissue disease-ILD 4
• Nintedanib is conditionally recommended for SSc-ILD 4
• JAK inhibitors and calcineurin inhibitors are conditionally recommended for idiopathic inflammatory myopathy-ILD 4

Progressive Pulmonary Fibrosis

Progressive pulmonary fibrosis is defined by at least two of: worsening respiratory symptoms, physiological evidence of progression on PFTs, and radiological evidence of progression on chest CT 4.

Risk Reduction Strategies

Implement the following risk reduction measures 3, 6:

• Smoking cessation is the single most effective strategy for slowing progression - use combination of pharmacotherapy (nicotine replacement, varenicline, or bupropion) and behavioral support 6
• Exposure remediation for identified environmental, occupational, or medication triggers 3, 6
• Age-appropriate vaccinations including influenza and pneumococcal vaccines to reduce risk of respiratory infections 3, 6

Follow-up and Monitoring

Establish systematic follow-up protocol 3, 4, 8:

• Serial PFTs (spirometry and DLCO) at 3-6 month intervals initially, then annually if stable 4
• Follow-up HRCT in 2-3 years after baseline CT 3, 8
• Earlier follow-up CT at 12 months may be appropriate if high-risk features present (definite fibrosis, subpleural fibrotic subtype, greater extent of abnormalities, abnormal PFTs, family history of pulmonary fibrosis, older age, smoking history) 3
• Regular clinical assessment for symptom progression 4
• Ambulatory desaturation testing every 3-12 months 4

Advanced Disease Management

For patients with advanced ILD 5:

• Structured exercise therapy reduces symptoms and improves 6-minute walk test distance 5
• Oxygen therapy reduces symptoms and improves quality of life in individuals who desaturate below 88% on 6-minute walk test 5
• Lung transplant should be considered for end-stage ILD - median survival is 5.2-6.7 years post-transplant compared to <2 years without transplant 5
• For pulmonary hypertension complicating end-stage fibrotic ILD, inhaled treprostinil improves walking distance and respiratory symptoms 5

Critical Pitfalls to Avoid

• Do not dismiss interstitial lung abnormalities as clinically insignificant even in asymptomatic patients - ILAs are associated with 66% increased risk of death and progression risk regardless of symptoms 4
• Do not delay smoking cessation intervention while focusing solely on pharmacologic treatments 6
• Do not fail to recognize disease progression due to infrequent monitoring 6
• Do not rely on chest radiography alone - up to 10% of ILD patients have normal chest X-rays 4